Fig. 7

The non-monotonic relationship between CHD8 protein levels, gene expression and brain size. The effects of gradual reductions in CHD8 protein levels to ~ 50% (heterozygous), ~ 35% (mild hypomorph), ~ 10% (severe hypomorph) and 0% (conditional knockout) on the transcription of neurodevelopmental, cell cycle and p53-regulated genes and brain size are depicted. CHD8 appears to function primarily as a positive regulator of neurodevelopmental genes via recruitment to H3K4me3-modified (yellow ball) histones (gray spool), presumably via enabling the recruitment of key transcription factors (TF). A sharp reduction in the expression of many of these genes (arrow) is only observed in E12.5 neocortex when CHD8 levels are reduced to below a threshold less than haploinsufficient levels. CHD8 appears to repress E2F-regulated cell cycle genes in this context, with significant induction only becoming evident at sub-haploinsufficient levels, although low expression increases (grey arrow) likely drives subtle increases in proliferation in the heterozygous state. Cell cycle genes are dysregulated in the opposite direction in the cKO, suggestive of non-monotonic effects (blue arrow). CHD8 can interact with p53 and histone 1 (H1), leading to stable heterochromatin formation and repression of p53 target genes. A few p53-regulated genes become activated in hypomorphic mice (grey arrow), but the majority remains fully repressed with de-repression only becoming evident upon complete CHD8 loss. Note the different CHD8 thresholds for different groups of genes (broken lines) and the non-monotonic effects on gene expression and over-all brain size